Thermodynamically stable form of (R)-3-[[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid (ramatroban)

ABSTRACT

The present invention relates to a thermodynamically stable modification of the active compound ramatroban of formula (I). The thermodynamically stable form is prepared either by melting of the metastable form and subsequent recrystallization or by seeding a solution of the metastable active compound with a seed crystal of the thermodynamically stable form. The thermodynamically stable active compound can be employed as an asthma agent.

The invention relates to a new form of ramatroban which is thermodynamically stable at room temperature, a process for its preparation, pharmaceuticals comprising this form, and their use in the control of diseases.

The preparation and use of ramatroban as a thromboxane A2 antagonist has already been disclosed in EP 242 518. U.S. Pat. No. 4,827,032, which is hereby incorporated by reference herein.

In the manner described there, ramatroban is obtained in the form of a crystal modification which is designated in the following text as modification II. Mod. II has a melting point of 137° C. and a malt enthalpy of 80 J/g (DSC, heating rate 2 K min⁻¹) and a characteristic X-ray diffractogram, IR spectrum, ¹³C-solid state NMR spectrum, FIR spectrum, Raman spectrum (FIGS. 1-6). It has now been found that Mod. II is metastable and therefore is not suitable for use in pharmaceutical formulations, such as, for example, solid and semi-solid preparations.

Surprisingly, a second modification of ramatroban has now been found which is thermodynamically stable and is also stable on storage after processing by means of suspensions and is therefore particularly suitable for use in pharmaceutical formulations, such as, for example, suspensions or creams, but also in other preparations which are prepared by means of suspended active compound, such as, for example, in aqueous granulation or wet-grinding. This new modification is designated in the following text as modification I. The present invention also relates to pharmaceutical formulations which contain ramatroban in the modification I as active substance. The formulation can contain one or more pharmaceutically acceptable auxiliaries, such as, for example, binders, solvents, fillers, etc.

J. Halbelian, W. McCrowne, J. Pharm. Sci. 58 (1969) 911, and J.-0. Henck et al., Pharm. Ind. 59 (1997) 165-169 disclose that when using a thermodynamically metastable polymorphic form in solid and semi-solid formulations, such as, for example, tablets, suspensions and ointments, the stable form can result. As an attendant phenomenon here, undesired crystal growth, changes in the bioavailability, caking, etc. are observed. The two crystal modifications of ramatroban differ in their solubility at-room temperature by 60%. By means of the use according to the invention of the stable modification I, it is ensured that no change in solubility can occur as a result of conversion. This increases the safety of preparations of ramatroban and the risk for the patients is thus reduced.

In comparison with Mod. II, Mod. I has a clearly distinguishable DSC thermogram, X-ray diffractogram, ¹³C-solid state NMR spectrum, FIR spectrum and Raman spectrum (FIGS. 1-6). The melting point of Mod. I is 151° C. and the melt enthalpy is 87 J/g.

The DSC and TGA thermograms were obtained using a DSC 7 and TGA 7 from Perkin-Elmer. The X-ray diffractograms were recorded in a Stoe transmission diffractometer. The IR, FIR and Raman spectra were recorded using Fourier IR spectrometers IFS 66 (IR), IFS 66v (FIR) and IFS 88 (Raman) from Bruker. The ¹³C-solid state NMR spectra were recorded using a Bruker MSL 300.

The crystal modification of ramatroban is employed in high purity in pharmaceutical formulations. For reasons of stability, Mod. I should not contain relatively large proportions of Mod. II. A grade of active compound with less than 10% of Mod. II, very particularly preferably with less than 5%, is preferred.

Mod. I is prepared by suspending ramatroban of modification II in water or inert substances, e.g. in lower alcohols, ketones or alkanes, seeding with crystals of Modification I and stirring until the desired degree of conversion is achieved, particularly preferably until quantitative conversion to Mod. I. As a rule, this conversion takes place at 20-50° C., preferably at 40° C. The crystals of Mod. I obtained are separated off and, to remove solvent present, dried to constant weight at room temperature in vacuo or at elevated temperature.

To prepare the seed crystals needed, the active compound is thoroughly melted and then rapidly cooled to room temperature. The amorphous form of the active compound thus obtained is suspended in an inert solvent at room temperature and stirred until it is completely converted into the thermodynamically stable crystal modification. The residue is filtered and dried to constant mass in vacuo.

EXAMPLES Example 1

Preparation of Seed Crystals from the Melt

About 300 mg of ramatroban of Mod. II are thoroughly melted and rapidly cooled to room temperature. The amorphous substance is suspended in 5 ml of ethanol/water (1:1) and the suspension is stirred at room temperature for 24 h. After the end of the stirring time, the suspension is filtered and the residue is dried in vacuo at room temperature.

Example 2

Seeding Process

130 g of ramatroban (Modification II) are dissolved in 650 g of n-butyl acetate and 15 g of water at about 40° C. 175 g of solvent are distilled off in vacuo at 40-45° C. The solution is then seeded with 1 g of ramatroban (Modification I) and a further 300 g of solvent are distilled off in vacuo at 40 to 45° C. The crystal suspension obtained is cooled to room temperature and stirred for a few hours. It is filtered off with suction, washed with n-butyl acetate and methyl tert-butyl ether and dried in vacuo at 50° C. About 100 g of ramatroban are obtained (Modification I).

Example 3

Precipitation Method

75 g of ramatroban (Modification II) are dissolved in 135 g of ethyl acetate with warming. 85 g of petroleum ether (35/60) are added dropwise at about 40° C. and the batch is seeded with 1 g of ramatroban (Modification I). The mixture is stirred at 40° C. for about 2-3 hours and then cooled to room temperature. A further 130 g of petroleum ether (35/60) are added to the suspension and it is additionally stirred at room temperature for about 5 hours. It is filtered off with suction, washed with 100 g of petroleum ether (35/60) and dried at 50° C. in vacuo. About 65 g of ramatroban (Modication I) are obtained.

Example 4

Conversion in Suspension 1

50 g of ramatroban (Modification II) are suspended in 75 g of n-butyl acetate and mixed with 0.5 g of ramatroban (Modification I). The mixture is stirred at room temperature for about 100 hours. It is then filtered off with suction, washed with methyl tert-butyl ether and dried at 50° C. in vacuo. About 40 g of ramatroban (Modification I) are obtained,

Example 5

Conversion in Suspension 2

About 0.5 g of Mod. I and II (mixing ratio about 1:1) are suspended in 8 ml of n-heptane and refluxed at about 80° C. After one week, the suspension is filtered and the residue is dried in vacuo at room temperature for one day.

Example 6

Production of Tablets

4590 g of microfine ramatroban of Mod. I are dispersed in a homogenizer with 9180 g of an aqueous HPC-L (367 g) and then filtered through a sieve having a 355 im mesh width. The granulation liquid is reacted in a granulator with 13,500 g of a premixed and preheated aqueous solution, consisting of 3162 g of lactose, 4860 g of HPC-L and 540 g of HPC-M, to form granules. The resulting granules are dried at 65° C. Pressing is then carried out in a rotary press to give tablets having a diameter of 9.0 mm.

TABLE 1 Differential Scanning Calorimetry Mod. I Mod. II Melting point 151 137 Melt enthalpy  87  80

TABLE 2 X-ray diffractometry Peak maxima [2 theta] Mod. I Mod. II 7.5 7.8 9.4 8.7 10.1 10.9 10.6 12.5 12.0 13.8 12.4 14.1 13.7 15.3 14.6 15.6 15.0 16.0 16.0 16.6 17.3 17.2 17.7 17.3 18.0 17.8 19.2 18.7 19.8 19.4 20.3 20.5 20.7 20.7 21.0 21.3 21.2 21.8 21.7 22.1 21.9 22.6 22.2 23.0 22.7 23.6 22.9 23.8 23.1 24.3 23.6 24.7 23.7 25.7 24.1 25.9 24.9 26.1 25.6 26.5 26.2 26.8 26.6 27.1 27.5 28.0 28.0 28.4 29.5 29.0 30.0 29.6 30.1 29.9 30.5 30.4 31.0 30.7 31.7 31.2 32.2 32.2 32.6 33.0 32.8 33.4 34.4 33.6 34.6 34.3 35.1 34.7 35.5 35.5 35.8 35.7 36.2 35.9 36.7 36.9 36.9 37.2 37.0 37.5 37.4 37.7

TABLE 3 IR spectroscopy Peak maxima [cm⁻¹] Mod. I Mod. II 3338 3298 3316 3244 3053 2943 2944 1697 1708 1615 1614 1591 1592 1495 1496 1466 1470 1447 1431 1416 1378 1379 1335 1357 1318 1327 1294 1305 1227 1292 1179 1274 1167 1240 1156 1228 1097 1213 1079 1186 1067 1164 1055 1151 1032 1103 1013 1088  972 1068  922 1055  868 1013  836  980  817  931  782  841  746  817  708  782  671  751  615  710  577  674  550  665  542  626  520  590  575  556  538  520

TABLE 4 ¹³C-Solid state NMR spectroscopy Peak maxima [ppm] Mod. I Mod. II 181.1 179.2 164.0 163.0 139.4 141.5 138.8 137.6 136.2 136.4 135.0 132.5 127.7 129.0 120.0 128.4 118.2 127.5 117.0 122.6 109.3 121.7 107.9 117.2 106.2 115.7 54.0 109.2 53.2 106.6 52.1 51.6 50.6 40.1 38.8 37.5 38.1 35.9 37.1 34.8 36.1 29.8 35.3 27.8 33.9 26.4 32.3 25.5 31.4 22.2 29.6 21.7 29.0 21.3 27.7 24.9 24.1 23.1 20.8 19.8

TABLE 5 FIR spectroscopy Peak maxima [cm⁻¹] Mod. I Mod. II 452 498 429 477 413 449 388 432 368 411 350 395 334 373 324 326 297 291 282 281 264 235 231 201 207 177 176 152 148 116 115 101 101  94  88  88

TABLE 6 Raman spectroscopy Peak maxima [cm⁻¹] Mod. I Mod. II 3080 3070 3069 3046 3056 2960 2955 2925 2925 2850 2898 1615 2851 1589 1613 1570 1580 1467 1566 1443 1471 1354 1438 1315 1412 1290 1369 1273 1293 1228 1277 1186 1236 1150 1180 1100 1165 1014 1155  981 1123  921 1091  847 1059  817 1012  794  973  693  928  628  833  567  817  520  785  435  743  330  682  287  629  227  574  91  521  334  283  199  122  90  82 

What is claimed is:
 1. Thermodynamically stable Modification I of ramatroban, comprising a characteristic selected from the group consisting of: (a) a melting point of 151° C. (DSC, 2 Kmin⁻¹); (b) an X-ray diffractogram having reflections at 10.1, 12.0 and 19.8 (2 theta); (c) an IR spectrum having peak maxima at 3338 cm⁻¹, 1708 cm⁻¹ and 1431 cm⁻¹; (d) a ¹³C-solid state NMR spectrum having peak maxima at 107.9 ppm, 118.2 ppm and 135.0 ppm; (e) an FIR spectrum having peak maxima at 264 cm⁻¹ and 207 cm⁻¹; and (f) a Raman spectrum having peak maxima at 3080 cm⁻¹, 1580 cm⁻¹ and 122 cm⁻¹.
 2. Process for the preparation of seed crystals of the thermodynamically stable Modification I of ramatroban according to claim 1, characterized in that the active compound is converted into the amorphous form by melting and rapid cooling and this is then converted into the stable Modification I by stirring in inert solvents.
 3. Process for the preparation of a thermodynamically stable form of ramatroban according to claim 1, characterized in that a thermodynamically metastable modification of ramatroban is suspended in water or inert organic solvents, seeded with the stable Modification I and the conversion is carried out until the desired degree of conversion is achieved.
 4. Pharmaceutical composition comprising a thermodynamically stable form of ramatroban according to claim
 1. 5. A method of treating a thromboxane A2 mediated disease or condition, comprising administering to a patient in need thereof the thermodynamically stable Modification I of ramatroban according to claim
 1. 6. The method of claim 5, wherein said thromboxane A2 mediated disease or condition is selected from the group consisting of thromboses, thromboembolisms, ischaemias, asthma and allergic reactions. 